Gaucher Disease ... (Gaucher disease) - Gen GBA

Gaucher disease is the most common disorder of lysosomal storage diseases, caused by inborn errors of metabolism with a heterogeneous pathophysiology and clinical manifestations. Epidemiological studies estimate a prevalence of 1 in 50,000 affected / 100,000 individuals in the general population, although in certain populations such as Ashkenazi Jews, is much higher (one affected every 500 / 1,000 individuals).

Clinically, Gaucher disease is divided into several types: Type 1, 2, 3, perinatal lethal type and cardiovascular type. Type 1, also called non - neuropathic Gaucher disease, is the most frequent, and corresponds to such 95% of patients, is characterized by not presenting neurological involvement and a high heterogeneity in signs and symptoms. The disease can be initiated in both childhood and adulthood. The main signs and symptoms include hepatosplenomegaly, anemia, easy bruising caused by thrombocytopenia, lung disease, and bone, such as bone pain, fractures and arthritis abnormalities. Type 2 and 3 disease known as neuronopathic forms, and characterized by problems affecting the central nervous system. In addition to the signs and symptoms described above, these types can cause abnormal eye movements, convulsions and brain damage. Type 2, called Gaucher disease Neuropathic Aguda, corresponds to the most severe form and is characterized by an early onset and early death, with a median survival of two years old. Type 3, called Gaucher disease Neuropathic subacute usually begins in childhood or juvenile stage and although corresponds to a severe form of the disease progresses more slowly than type 2, can survive to adulthood (half - life 30 -40 years).

The most severe type of Gaucher disease is known as the perinatal lethal type, which causes severe or potentially fatal complications that begin before birth or in infancy. The characteristics of the perinatal lethal form may include a swelling caused by fetal hydrops, ichthyosis or other skin anomalies, hepatosplenomegaly, distinctive facial features and severe neurological problems. As the name suggests, most newborns with perinatal lethal form of Gaucher disease survive only a few days after birth. Another form of Gaucher disease is known as the cardiovascular type because mainly affects the heart, causing heart valves calcify. Individuals with cardiovascular form of Gaucher disease may also have ocular abnormalities, bone disease, and mild splenomegaly.

Gaucher disease is due to a partial or total deficiency of a specific enzyme called beta-glucocerebrosidase, encoded from GBA gene, located on the long arm of chromosome 1 (1q21). In healthy individuals, the beta-glucocerebrosidase decomposes glucocerebroside (glucosyl ceramide), a glycolipid from the erythrocyte membrane and worn in the lysosomes of monocytes and macrophages leukocytes. In individuals with Gaucher disease this decomposition is insufficient, causing the substrate accumulation in monocytes and macrophages. These cells filled with lipids, are termed "Gaucher cells" and have a characteristic appearance with considerable increase in its size and survival. Gradually they accumulate in large quantities in the organs and tissues which are normally found macrophages, which explains the multisystemic nature of signs and symptoms. The most frequently affected organs include liver, spleen, bone marrow and the central nervous system (CNS). This buildup can cause disruption of normal functioning of these organs, also can cause irreparable damage. Moreover, Gaucher cells can stimulate the release of cytokines (Interleukin 6 and 10 -IL6 and IL10- and Tumor Necrosis Factor alpha -TNF?-), which may contribute to the pathogenesis of Gaucher disease.

Until now we found over 240 mutations that reduce partly or completely the catalytic activity of the enzyme and reduce their stability and half - life. Most of the mutations responsible for the disease change a single amino acid beta-glucocerebrosidase, altering the structure of the enzyme preventing it from functioning normally. Other mutations deleted or inserted genetic material or coding result of an abnormally short, nonfunctional version of the enzyme. All these mutations greatly reduce or eliminate the activity of beta-glucocerebrosidase in cells. Consequently, glucocerebrosidase not broken down properly. This molecule and related substances can accumulate in macrophages in the spleen, liver, bone marrow and other organs. Abnormal accumulation and storage of these substances damage the tissues and organs, leading to the characteristic features of Gaucher disease.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Gaucher disease, by complete PCR amplification of the exons of the GBA gene, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample). In case of prenatal diagnosis, mniótico liquid.